As drug delivery systems for transferring a necessary amount of an administered drug to a desired tissue when needed, methods using a fine particles such as a liposome, an emulsion, a micell, a fine particle crystal, a microcapsule, a microsphere or the like as a drug carrier are known.
For example, liposomes are used as drug carriers for antitumor agents, antiinflammatory agents and the like. It is known that, when administered into a vein, the liposomes are trapped in the lung, liver, spleen or the like and rapidly disappear from blood. Therefore, it is difficult for the liposomes to efficiently transfer the agents to a tumor or inflamed part in a target region other than the lung, liver, and spleen. Thus, various attempts have been made to increase retention of the liposomes in blood, including chemical modification of the liposomes with polyethylene glycol (PEG), and the like. For example, it is known that liposomes modified with surface modifiers comprising PEG derivatives (PEG-modified liposomes) show remarkably high retention in blood (for example, Japanese Patent No. 2667051, Japanese Published Examined Patent Application No. 20857/95, Japanese Patent No. 2948246 and the like). Also, it is known that liposomes modified with surface modifiers comprising polyglycerin derivatives (polyglycerin-modified liposomes) are increased retention in blood (for example, Japanese Published Unexamined Patent Application No. 228012/94).
However, the PEG-modified liposomes have several disadvantages in view of use as the drug carrier. For example, although a PEG-modified liposome can efficiently transfer a drug to a tumor cell, the PEG on the surface of the liposome has a large steric hindrance to inhibit interaction between the drug and the tumor cell to thereby prevent the drug from efficiently moving into the tumor cell (Biochimica et Biophysica Acta, 1558, 1-13 (2002)). Also, it is known that when a PEG-modified liposome is repeatedly administered, the retention thereof in blood is reduced (Journal of Controlled Release, 88, 35-42 (2003) and Journal of Pharmacology and Experimental Therapeutics, 292, 1071-1079 (2000)). Furthermore, in a PEG-modified liposome containing a monoclonal antibody, the PEG inhibits the cell recognition ability of the antibody, whereby there is a difficulty in active targeting by the PEG-modified liposome (Biochimica et Biophysica Acta, 1062, 142-148 (1991)). Moreover, it is possible that the stability of a liposome membrane is reduced by introducing a PEG to a lipid of the liposome, whereby a drug encapsulated in the liposome easily leaks.
Although the polyglycerin-modified liposomes have been developed as ones with high retention in blood instead of the PEG-modified liposomes, they are insufficient in the retention, which is only twice as high as unmodified liposomes.
Under such circumstances, there is a demand for a novel drug carrier as a substitute to the PEG-modified liposomes.